Explanation of the unpredictable hepatotoxicity following use of commonly employed halogenated inhalation anesthetics remains the keystone of investigation. The mechanism of chloroform toxicity has now been well defined during the course of these investigations, and there are many indications that halothane may be somewhat parallel in mechanism. It has been determind that debromination of halothane does not proceed through cytochrome P-450 by previous experiments in this laboratory. A debrominated, reduced derivative of halothane has been synthesized in the laboratory (CF3CH2Cl). This compound appears to produce hepatotoxicity in appropriate dosages in the rat in preliminary studies. Investigations this coming year will be estimated at: 1) determination if this necrosis is lipoperoxidative in nature; 2) if such a reductive pathway is inducible, particularly by polychlorobiphenyl; 3) if this necrosis can be prevented or augmented by free radical scavengers such as cysteamine. Many studies need to be accomplished to cement this mechanism of anesthetic hepatotoxicity such that it can be applied to human toxicology in the future. Such studies will include: covalent bonding of metabolic intermediates to microsomal protein and lipid; effects of antioxidant (GSH and tocopherol) levels; microsomal enzyme contents; and temporal assay of products of lipoperoxidation (diene conjugates, malonaldehyde, and fluorescent pigments).